Aerosol formulations of delta tetrahydrocannabinol

ABSTRACT

The application discloses an aerosol formulation comprising Δ 8  Tetrahydrocannabinol for use as a medicine, and the use of Δ 8  Tetrahydrocannabinol to treat a condition selected from pain, appetite loss, multiple sclerosis and asthma.

FIELD OF THE INVENTION

The invention is directed to the therapeutic use of Δ⁸Tetrahydrocannabinol (Δ⁸ THC). In particular, the invention provides Δ⁸THC formulations suitable for administration to the buccal or nasalmucosa or the pulmonary airways. Such Δ⁸ THC formulations are useful forthe reduction, elimination or prevention of pain associated with anymedical condition; the stimulation of appetite; the reduction,elimination or prevention of nausea; the reduction, elimination orprevention of vomiting (antiemetic properties); the relaxation of muscletissue (e.g., for the treatment of multiple sclerosis).

SUMMARY OF THE RELATED ART

Currently there is much interest in the possible medical use of Cannabisor its natural constituents. In Great Britain, for example, two House ofLords reports from 1999 and 2001 have both recommended furtherinvestigation as to whether the anecdotal (i.e., not scientificallyproved) reports from certain patients with multiple sclerosis and otherlong term painful or debilitating diseases have a genuine basis.

Cannabis use is centuries old, particularly in China and India, althoughthe abuse (mostly in the West) is of more recent origin and dates backonly about 100 years.

There have been many arguments as to the dangers of Cannabis and itsaddictive potential, however a general consensus seems to be growingthat it is probably no worse than tobacco in terms of addiction althoughthere is a potential for longer term psychosis if large doses are takenfor the immediate “high”. The common method of taking Cannabis issmoking, but this gives rise to similar bad effects on the lung fromtars and other components as for tobacco.

Currently there are three approaches to the investigation of possiblemedical uses for cannabinoids (the name for the group of “active”molecules in Cannabis).

One is to try to standardize an extract from a plant or mixtures ofplants. Much of the current work both in the UK and US is based on theuse of a “Cannabis Oil” extracted from plants. This contains a mixtureof natural molecules, some of which are at present not characterized.The extract must be standardized which is difficult to achieve even inrigorously controlled growing conditions and it is very difficult if notimpossible to purify the active constituents away from plant materialssuch waxes, sterols etc.

The second is to try to develop new synthetic molecules based on thestructures of the natural cannabinoids hopefully without some of thepossible psychotropic side effects. The synthesis of new molecules isbeing investigated by a number of academic centers but is extremelycostly to complete and bring to market. The generally accepted cost tocarry out all the chemistry, pharmacology, clinical trials etc. to bringa new drug to market is usually quoted at about $300 million and this byno means guarantees success.

The third is to synthesize synthetic equivalents of some of the naturalcannabinoid molecules. The main active constituent of Cannabis is nowknown to be THC (tetrahydrocannabinol) with two other major componentsCannabidiol and Cannabinol depending on the plant used and the growingconditions.

There are then many other minor components some of which have beenidentified and some of which have not. These structures are shown below.

A major problem associated with the medicinal use of cannabinoidsentails the method for administering said cannabinoids. Smoking Cannabisleaves or resin for medical use would not be acceptable in manycountries e.g., UK, as it is not standardized, difficult to control thedosage and would result in similar tars etc., depositing in the lung asfrom tobacco smoking.

There are some current trials using capsules of Cannabis extracts or itssynthetic components but these are known to be less than desirable ascannabinoids are rapidly metabolised in the body when given orally intothe stomach (so called “First Pass Metabolism”) and large doses areneeded to get possible active molecules into the blood stream inadequate amounts. This leaves large amounts of metabolites, some ofwhich must have clinical activity of some sort and may well give rise tosome of the unwanted side effects.

Others are using a standardized extract given under the tongue in themouth where the active components are absorbed directly into the veinsin the mouth so avoiding the “First Pass Metabolism”, they use aspecially formulated spray to dose the drug.

Still others have tried similar approaches. While mixtures of activemolecules were produced, it was impossible to remove all the associatedplant material, which was of a waxy nature. This would make themunsuitable for administration directly into the lungs as the removal ofwaxy material from the lungs would be problematic and may well lead to abuild up of wax in the lung with all the long term problems and dangersthis may involve.

One possible approach to the problem entails the possibility of usingchemically synthesized molecules or mixtures of the naturally occurringcannabinoids. This is because there is some limited toxicity dataalready available on such compounds. For example, Abrahamov, et al.,(Life Sciences 56: 2097-2102, -1995 and U.S. Pat. No. 5,605,928) haveshown promising results using a synthetic version of the THC in childrenwith cancer where the incidence of nausea was greatly reduced with nosignificant side effects.

This molecule is called Δ⁸ THC in comparison the naturally occurring Δ⁹THC, which as mentioned earlier, is the main naturally occurring activeconstituent of Cannabis. The structures are shown below and the twomolecules can be seen to differ only by the position of a double bondfrom 8 to 9.

Δ⁸ THC is reportedly easier to synthesize the Δ⁹ THC. It exists as anoil at ambient temperature.

The literature has many anecdotal references to possible medicinal usesof Cannabis, for example: Relief of Pain (post operatively, Oncological,Phantom Limb etc), Multiple Sclerosis, Anti-nausea, Appetite.Stimulation, Asthma etc.

Pain relief in terminal oncology is now widely accepted to be the mainconcern of the physician and the main component of this is morphinenormally given as delayed release tablets (or by injection or infusion).In the terminal stages of the disease, it often becomes difficult forthe patient to swallow, either due to GI tract obstruction or anassociated nausea caused by the disease or by some of the anti-cancertreatments, and so an aerosol treatment directly into the lungs mightwell be of significant value.

The present invention addresses such problems associated with medicinalcannabinoid administration by providing an aerosol formulation where theprinciple active medicament is Δ⁸ Tetrahydrocannabinol.

SUMMARY OF THE INVENTION

The present invention provides aerosol formulations for the medicinaladministration of Δ⁸ Tetrahydrocannabinol. In a second aspect, theinvention provides a method for treating patients to alleviate thesymptoms associated with a number of disease, states using Δ⁸Tetrahydrocannabinol.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention provides Δ⁸ Tetrahydrocannabinol formulations andmethods for treating patients to alleviate the symptoms associated witha number of disease states. Therefore, an object of the invention is (a)the reduction, elimination or prevention of pain associated with anymedical condition; (b) the stimulation of appetite; (c) the reduction,elimination or prevention of nausea; (d) the reduction, elimination orprevention of vomiting (antimetic properties); (e) the relaxation ofmuscle tissue (e.g. for the treatment of multiple sclerosis).

The active medicament for these formulations and methods is Δ⁸Tetrahydrocannabinol (Δ⁸ THC).

The present invention provides aerosol formulations for the medicinaladministration of Δ⁸ Tetrahydrocannabinol and novel medicinal uses of Δ⁸Tetrahydrocannabinol. The term Δ⁸ Tetrahydrocannabinol (Δ⁸ THC)designates Δ⁸ Tetrahydrocannabinol and prodrugs (hereinaftercollectively designated as “Δ⁸ THC moieties”).

According to one aspect, the present invention provides the use of Δ⁸Tetrahydrocannabinol in the manufacture of an aerosol formulation formedicinal administration to a patient from an aerosol delivery device.

According to an alternative aspect, the present invention provides amethod of treating a mammal suffering from a condition indicatingtreatment with a Δ⁸ Tetrahydrocannabinol, which comprises administeringan aerosolized aerosol formulation containing a therapeuticallyeffective amount of Δ⁸ Tetrahydrocannabinol to the mammal.

The condition may be any medical-condition indicating treatment with Δ⁸Tetrahydrocannabinol, for example a condition selected from pain,nausea, vomiting, appetite loss, multiple sclerosis and asthma.

In one embodiment of the invention, the patient (or mammal) may be acancer patient undergoing chemotherapy, and the condition is selectedfrom pain, nausea, vomiting and appetite loss.

Particular mention may be made of the case where the condition is painassociated with phantom limb syndrome.

Particular mention may also be made of the case where the condition isappetite loss associated with anorexia nervosa.

In one embodiment, the aerosol formulation is for administration to thelungs of the patient.

In another embodiment, the aerosol formulation is for administration tothe buccal or nasal mucosa of the patient.

According to another aspect, the present invention provides an aerosoldelivery device containing an aerosol formulation comprising Δ⁸Tetrahydrocannabinol.

According to yet another aspect, the present invention provides anaerosol formulation for use in an aersol delivery device, whichcomprises Δ⁸ Tetrahydrocannabinol.

Preferably, the aerosol formulation further comprises a propellant.

The propellant is preferably selected from 1,1,1,2-tetrafluoroethane(HFA 143a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227).

Preferably, the aerosol formulation further comprises ethanol as asolvent.

For inhalation, the formulations of the present invention may bedelivered via any inhalation methods known to those skilled in the art.Such inhalation methods and devices include, but are not limited to,metered dose inhalers with propellants such as CFC or HFA or propellantsthat are physiologically and environmentally acceptable. Other includeddevices are breath-operated inhalers, multidose dry powder inhalers andaerosol nebulizers. One preferred way of administering the formulationsof the invention is by using conventional actuators. The term “actuator”as used in the present invention includes all types of actuatorspresently available including but not limited to standard metered doseinhalers or breath operated inhalers. Breath-actuated devices are alsoknown, and have been the subject of many patent applications. Thus, forexample, GB 1288971; GB 1297993; GB 1335378; GB 1383761; GB 1392192; GB1413285; WO85/01880; GB 2204799; U.S. Pat. No. 4,803,978 and EP 018628OAdescribe inhalation-actuated dispensing devices for use with apressurized aerosol-dispensing container.

In a preferred embodiment of the invention, administration is effectedby a means of a pump or squeeze-actuated nebulizer. In more preferredembodiments of the invention administration is effected by means of ametered dose inhaler or an aerosol dispenser.

Formulations of the present invention may conveniently be present inunit dosage form and may be prepared by conventional pharmaceuticaltechniques as discussed above. Such techniques include the step ofbringing into association the Δ⁸ THC moiety and the pharmaceuticalcarrier(s) or excipient(s) In general the formulations are prepared byuniformly and intimately bringing into association the active ingredientwith liquid carriers or finely divided solid carriers or both, and then,if necessary, shaping the product.

Formulations-suitable for administration by inhalation includesformulations of Δ⁸ THC, in a form that can be dispensed by suchinhalation devices known to those in the art. Such formulations mayinclude carriers such as powders and aerosols. The inhalant compositionsused in the present invention may comprise liquid or powderedcompositions containing the active ingredient that are suitable fornebulization and intrabronchial use, or aerosol compositionsadministered via an aerosol unit dispensing metered doses.

Aerosol formulations for use in the subject method would typicallyinclude in addition to a therapeutically effective amount of a Δ⁸ THCmoiety and at least one propellant. The formulations of the inventionsmay be solutions or suspensions of the Δ⁸ THC moieties.

Those of skill will appreciate that the amount of the Δ⁸ THC moiety maybe tailored based on the solubility of the active ingredients,stability, commercial necessities, and medical requirements. Preferredformulations comprise from about 0.01 to about 10% of Δ⁸ THC moiety.More preferred formulations include from about 0.05 to about 6%. Δ⁸ THCmoieties according to both aspects of the invention have been preparedfrom natural CBD by cyclization and purified by chromatography (seee.g., Abrahamov et al, supra). Preferably the Δ⁸ THC moiety issynthesized to a acceptable pharmaceutical purity (greater than 99%pure).

Preferred propellants include hydrofluoroalkanes (HFAs; e.g., HFA 134a,HFA 227, or a blend thereof) or chlorofluorocarbons (CFCs).

In some embodiments, the formulation includes additional activecomponents such as, forexample, another cannabinoid. In particularlypreferred embodiments, the additional cannabinoid is cannabidiol (CBD).CBD is commercially available. optionally, the formulations may containsurfactants and co-solvents and may be filled into conventional aerosolcontainers that are closed by a suitable metering valve. In aparticularly preferred embodiment, the formulation may include ethanol.

The following non-limiting examples of formulations are representativefor the purposes of illustration only: Δ⁸ THC moiety CBD Ethanol HFA134a HFA 227 % (w/w) % (w/w) % (w/w) % (w/w) % (w/w) 0.02 0 0 99.98 00.02 0 2.0 0 97.98 0.05 0.05 0 99.9 0 1.0 0.5 10.0 48.5 40.0

The formulations according to the invention may optionally include anyof the well known pharmaceutically acceptable carriers includingdiluents and excipients (see Remington's Pharmaceutical Sciences,18^(th) Ed., Gennaro, Mack Publishing Co., Easton, Pa. (1990) andRemington: The Science and Practice of Pharmacy, Lippincott, Williams &Wilkins (1995).

Suitable liquid compositions comprise the active ingredient in anaqueous, pharmaceutically acceptable inhalant solvent, e.g., isotonicsaline or bacteriostatic water. The solutions are administered by meansof a pump or squeeze-activated nebulized spray dispenser, or by anyother conventional means for causing or enabling the requisite dosageamount of the liquid composition to be inhaled into the patient's lungs.

Suitable powder compositions include, by way of illustration; powderedpreparations of the active ingredient thoroughly intermixed with lactoseor other inert powders acceptable for intrabronchial administration. Thepowder compositions can be administered via a dispenser, including, butnot limited to, an aerosol dispenser or encased in a breakable capsulewhich may be inserted by the patient into a device that punctures thecapsule and blows the powder out in a steady stream suitable forinhalation.

Formulations suitable for topical administration in the mouth includelozenges comprising the ingredients in a flavored basis, usually sucroseand acacia or tragacanth; pastilles comprising the active ingredient inan inert basis such as gelatin and glycerin, or sucrose and acacia; andmouthwashes comprising the ingredient to be administered in a suitableliquid carrier.

Formulations suitable for topical administration to the skin may bepresented as ointments, creams, gels, lotions, and pastes comprising theingredient to be administered in a pharmaceutical acceptable carrier. Apreferred topical delivery system is a transdermal patch containing theingredient to be administered.

Formulations for rectal administration may be prepared as a suppositorywith a suitable base comprising, such as, for example, cocoa butter.

Formulations for nasal administration, wherein the carrier is a solid,include a coarse powder having a particle size, for example, in therange of 20 to 500 microns which is administered in the manner in whichsnuff is administered, i.e., by rapid inhalation through the nasalpassage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid, foradministration for example via a nasal spray, aerosol, or as nasaldrops, include aqueous or oily solutions of the active ingredient.

Formulations suitable for vaginal administration may be presented aspessaries, suppositories, tampons, creams, gels, pastes, foams or sprayformulations containing, in addition to the active ingredients, suchcarriers as are known in the art to be appropriate.

Formulations suitable for parental administration include aqueous andnon-aqueous sterile, injection solutions which may contain antioxidants,stabilizers, buffers, bacteriostats, and

In a second aspect, the invention provides methods for treating a mammalto alleviate the symptoms associated with a number of disease states.Therefore, an object of the invention is (a) the reduction, eliminationor prevention of pain associated with any medical condition; (b) thestimulation of appetite; (c) the reduction, elimination or prevention ofnausea; (d): the reduction, elimination or prevention of vomiting(anti-emetic properties.); (e) the relaxation of muscle tissue (e.g.,for the treatment of multiple sclerosis).

The term “mammal” is used to designate any warm-blooded animal.Accordingly, the invention is useful for medical as well as veterinaryuses.

The formulations used are as described for the first aspect of theinvention. Therapeutically effective amounts of the formulations areadministered to mammals potentially benefiting from treatment with a Δ⁸THC moiety for a therapeutically effective period of time. Dosages willdepend on the condition being treated, the particular compound, andother clinical factors such as weight and condition of the mammal andthe route of administration.

The term “therapeutically effective amount” and “therapeuticallyeffective period of time” are used to denote treatments at dosages andfor periods effective to achieve the therapeutic result sought.Furthermore, one of skill will appreciate that the therapeuticallyeffective amount of Δ⁸ THC moiety may be lowered or increased by finetuning and altering the amount of the other component. The inventiontherefore provides a method to tailor the administration/treatment tothe particular exigencies specific to a given mammal. Therapeuticallyeffective ranges may be easily determined for example empirically bystarting at relatively low amounts and by step-wise increments withconcurrent evaluation of inhibition.

EXAMPLES Example I

To identify dose-limiting toxicity, healthy human volunteers areadministered Δ⁸ Tetrahydrocannibinol aerosol formulations according tothe invention at low dosages which are incrementally escalated whilemonitoring the subjects for dose-limiting side effects (such aspsychotropic symptoms)

Example II

To identify therapeutically effective amounts and times, terminaloncology patients are administered Δ⁸ Tetrahydrocannibinol aerosolformulations according to the invention at low dosages which areincrementally escalated until either the maximum acceptable level inExample I is reached, or the side effects in patients become too high,or sufficient efficacy is seen that increasing the dose further isunnecessary.

The following examples illustrate alternative aerosol formulations.

Example 1

Ingredient Weight in g Ethanol 0.10 P-134a 2.02 delta-8-THC 0.01 LipoidS100 ™ 0.05Lipoid S100™ is a phospholipid.

Example 2

Ingredient Weight in g Ethanol 0.09 P-134a 1.83 delta-8-THC 0.01 Brij ™0.02Brij™ is a Lauryl Polyoxyethylene

Example 3

Ingredient Weight in g Ethanol 0.20 P-134a 3.80 delta-8-THC 0.01Salbutamol Sulphate 0.01

1. Use of Δ⁸ Tetrahydrocannabinol in the manufacture of an aerosolformulation for medicinal administration to a patient from an aerosoldelivery device.
 2. Use as claimed in claim 1, in which the patient issuffering from a condition selected from pain, nausea, vomiting,appetite loss, multiple sclerosis and asthma.
 3. Use as claimed in claim2, in which the patient is a cancer patient undergoing chemotherapy, andthe condition is selected from pain, nausea, vomiting and appetite loss.4. Use as claimed in claim 2, in which the condition is pain associatedwith phantom limb syndrome.
 5. Use as claimed in claim 2, in which thecondition is appetite loss associated with anorexia nervosa.
 6. Use asclaimed in any one of claims 1 to 5, in which the aerosol formulation isfor administration to the lungs of the patient.
 7. Use as claimed in anyone of claims 1 to 5, in which the aerosol formulation is foradministration to the buccal or nasal mucosa of the patient.
 8. Anaerosol delivery device containing an aerosol formulation comprising Δ⁸Tetrahydrocannabinol.
 9. A device as claimed in claim 8, which is ametered dose inhaler and in which the aerosol formulation furthercomprises a propellant.
 10. A device as claimed in claim 9, in which thepropellant is selected from 1,1,1,2-tetrafluoroethane and1,1,1,2,3,3,3-heptafluoropropane.
 11. A device as claimed in claim 9 orclaim 10, in which the aerosol formulation further comprises ethanol asa solvent.
 12. An aerosol formulation for use in an aerosol deliverydevice, which comprises Δ⁸ Tetrahydrocannabinol.
 13. An aerosolformulation as claimed in claim 12, which further comprises apropellant.
 14. An aerosol formulation as claimed in claim 13, in whichthe propellant is selected from 1,1,1,2-tetrafluoroethane and1,1,1,2,3,3,3-heptafluoropropane.
 15. An aerosol formulation as claimedin claim 13 or claim 14, which further comprises ethanol as a solvent.16. A method of treating a mammal suffering from a condition indicatingtreatment with a Δ⁸ Tetrahydrocannabinol, which comprises administeringan aerosolized aerosol formulation containing a therapeuticallyeffective amount of Δ⁸ Tetrahydrocannabinol to the mammal.
 17. A methodas claimed in claim 16, in which the mammal is suffering from acondition selected from pain, nausea, vomiting, appetite loss, multiplesclerosis and asthma.
 18. A method as claimed in claim 17, in which themammal is a cancer patient undergoing chemotherapy, and the condition isselected from pain, nausea, vomiting and appetite loss.
 19. A method asclaimed in claim 17, in which the condition is pain associated withphantom limb syndrome.
 20. A method as claimed in claim 17, in which thecondition is appetite loss associated with anorexia nervosa.
 21. Amethod as claimed in claim in 16, in which the aerosolized aerosolformulation is administered to the lungs of the mammal.
 22. A method asclaimed in claim in 16, in which the aerosolized aerosol formulation isadministered to the buccal or nasal mucosa of the mammal.